Natural killer cells are essential for the ability of BRAF inhibitors to control BRAFV600E-mutant metastatic melanoma
Published version of a preprint
Abstract
BRAF(V600E) is a major oncogenic mutation found in approximately 50% of human melanoma that confers constitutive activation of the MAPK pathway and increased melanoma growth. Inhibition of BRAF(V600E) by oncogene targeting therapy increases overall survival of patients with melanoma, but is unable to produce many durable responses. Adaptive drug resistance remains the main limitation to BRAF(V600E) inhibitor clinical efficacy and immune-based strategies could be useful to overcome disease relapse. Tumor microenvironment greatly differs between visceral metastasis and primary cutaneous melanoma, and the mechanisms involved in the antimetastatic efficacy of BRAF(V600E) inhibitors remain to be determined. To address this question, we developed a metastatic BRAF(V600E)-mutant melanoma cell line and demonstrated that the antimetastatic properties of BRAF inhibitor PLX4720 (a research analogue of vemurafenib) require host natural killer (NK) cells and perforin. Indeed, PLX4720 not only directly limited BRAF(V600E)-induced tumor cell proliferation, but also affected NK cell functions. We showed that PLX4720 increases the phosphorylation of ERK1/2, CD69 expression, and proliferation of mouse NK cells in vitro. NK cell frequencies were significantly enhanced by PLX4720 specifically in the lungs of mice with BRAF(V600E) lung metastases. Furthermore, PLX4720 also increased human NK cell pERK1/2, CD69 expression, and IFNγ release in the context of anti-NKp30 and IL2 stimulation. Overall, this study supports the idea that additional NK cell-based immunotherapy (by checkpoint blockade or agonists or cytokines) may combine well with BRAF(V600E) inhibitor therapy to promote more durable responses in melanoma.
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The BRAF inhibitor PLX4720 has immunostimulatory effects on NK cells, increasing CD69 expression and IFNG secretion when IL2 is present.
“the BRAF inhibitor PLX4720 reportedly mediates immunostimulatory effects on NK cells by favoring CD69 expression and boosting IFNG secretion in the context of IL2 stimulation (Ferrari de Andrade et al., 2014)”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Ferrari de Andrade et al., 2014
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- Authors
- Ferrari de Andrade, L., Ngiow, S. F., Stannard, K., Rusakiewicz, S., Kalimutho, M., Khanna, K. K., Tey, S.-K., Takeda, K., Zitvogel, L., Martinet, L., & Smyth, M. J.
- Affiliations
- 1Laboratorio de Pesquisa em Células Inflamatórias e Neoplásicas Group, Universidade Federal do Paraná, Curitiba, Paraná, Brazil.
- QIMR Berghofer Medical Research Institute (AU)
- Inserm (FR)
- Juntendo University (JP)
- Université Paris-Sud (FR)
- The University of Queensland (AU)
- Corresponding author
- Smyth, Mark J.
- ORCID
- Venue
- Cancer Research
- Published
- 2014-12-14
- Volume
- 74
- Issue
- 24
- Pages
- 7298-7308
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2037723794
- Cited by
- 105
- References
- 37
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 9 · 2022: 7 · 2021: 9 · 2020: 14 · 2019: 7 · 2018: 9 · 2017: 13 · 2016: 18 · 2015: 14 · 2014: 1
- FWCI
- 6.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- natural killer cells, BRAF V600E mutation, metastatic melanoma, BRAF inhibitors, PLX4720, vemurafenib, perforin, ERK1/2 phosphorylation, CD69, lung metastasis, tumor microenvironment, adaptive drug resistance, NK cell therapy, interferon-gamma, MAPK signaling
- MeSH terms
- Animals, Humans, Immunotherapy, Killer Cells, Natural, Melanoma, Mutation, Neoplasm Metastasis, Signal Transduction, Drug Resistance, Neoplasm, Cell Line, Tumor, Proto-Oncogene Proteins B-raf, Cell Proliferation, Mice
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